ABSTRACT
Bone research is limited by available methods to detect changes in bone metabolism.
While dual x-ray absorptiometry is rather insensitive, biochemical markers are subject to significant intra-individual variation. Within the presented study, we evaluated isotopic labeling of bone using 41Ca, a long living radiotracer, as an alternative approach. After successful labeling of the skeleton, changes in the systematics of urinary 41Ca excretion are expected to directly reflect changes in bone Ca metabolism.
A minute amount of 41Ca (100 nCi) was administered orally to 22 postmenopausal
women. Kinetics of tracer excretion were assessed by monitoring changes in urinary
41Ca/40Ca isotope ratios up to 700 days post dosing using accelerator mass
spectrometry and resonance ionization mass spectrometry. Isotopic labeling of the
skeleton was evaluated by two different approaches: a) urinary 41Ca data were fitted for each individual to an established function consisting of an exponential- and a power law term; b) 41Ca data were analyzed by population pharmacokinetic (NONMEM) analysis to identify a compartmental model for describing urinary 41Ca tracer kinetics. A linear three compartment model with a central compartment and two sequential peripheral compartments was found to best fit the 41Ca data. Fits based on the use of the combined exponential/power-law for describing urinary tracer excretion showed substantially higher deviations between predicted and measured values than fits based on the compartmental modeling approach.
By establishing the urinary 41Ca excretion pattern using data points up to day 500 and
extrapolation of these curves up to day 700, it was found that calculated 41Ca/40Ca
isotope ratios in urine were significantly lower than observed 41Ca/40Ca isotope ratios for both techniques. Compartmental analysis can overcome this limitation. By introducing an intervention as an additional variable into the model and identifying relative changes in transfer rates between compartments, inaccuracies in the underlying model cancel out for labeling and intervention period.
Changes in tracer distribution between compartments were modelled based on identified kinetic parameters. While bone formation and resorption can, in principle, be assessed by monitoring urinary 41Ca excretion over the first weeks post-dosing, assessment of an intervention effect is more reliable ca. 150 days post-dosing when excreted traceroriginates mainly from bone.